The Retinoic acid-related orphan receptor (ROR) gene family is part of the nuclear hormone receptor super-family and consists of three members ROR alpha, ROR beta and ROR gamma (RORα, RORβ and RORγ). Each ROR gene is expressed in different isoforms; the isoforms differ in their pattern of tissue-specific expression and can regulate distinct physiological processes and target genes. More specifically two isoforms of RORγ have been identified; RORγ1 and RORγ2 (known as RORγt). RORγ1 is expressed in multiple tissues, such as heart, brain, kidney, lung, liver and muscle; whereas RORγt is restricted to the cells of the immune system and is expressed in lymphoid organs, such as the thymus (Jetten, A. M.; Adv. Dev. Biol. (2006), 16, 313-355).
RORγt has been shown to be crucial for the development of T helper 17 cells (TH17 cells) (Ivanov et. al., Cell (2006), 126, 1121-1133). TH17 cells, which produce IL-17, IL-21 and IL-22, have an essential role in the development of many autoimmune and inflammatory disorders, such as multiple sclerosis, psoriasis and rheumatoid arthritis. (Betelli, E. et al., Nature Immunol. (2007), 8, 345-350; Fouser, L. et al. Immunol. Rev. (2008), 226, 87-102); suggesting that development of RORγ modulators may be beneficial for treatment of autoimmune and inflammatory diseases (Kojetin, D. et al.; Nature Rev Drug Discovery (2014) 13, 197-215).
Recently, Proof-of-Concept was shown with an oral RORγt inhibitor (VTP 43742) in a Phase 2a clinical trial in psoriatic patients.
Several other compounds modulating RORγt have been reported, for example; WO2014/086894 discloses ‘Modulators of the retinoid-related orphan receptor gamma (ROR-gamma) for use in the treatment of autoimmune and inflammatory diseases.’ WO2015/180612, WO2015/180613 and WO2015/180614 disclose novel retinoid-related orphan receptor gamma (ROR-gamma) modulators and their use in the treatment of autoimmune and inflammatory diseases.
Thus it is desirable to provide compounds that modulate the activity of RORγ for use in the treatment of autoimmune and inflammatory disorders.